Adrenocortical carcinoma (ACC) is a highly malignant tumor with an incidence of 1 to 1.6 cases per million per year. It presents with metastatic disease in up to 40% of cases. In advanced or recurrent disease treatment options are limited, and therapies using agents such as mitotane, cisplatin and adriamycin effect a tumor response rate of less than 30%. Thyroid carcinoma is the most common endocrine malignancy, accounting for the majority of deaths from endocrine cancers. Each year in the US, approximately 14,000 new cases of thyroid carcinoma are diagnosed and 1200 patients die from this disease. Conventional therapy consists of surgical resection and radioiodine (131I) therapy. However, for poorly differentiated thyroid carcinomas (PDTCs) and anaplastic carcinomas that do not concentrate iodine, 131I therapy is ineffective. In these patients, therapeutic options are few and largely ineffective. finally pheochromocytomas have emerged as an endocrine malignancy with few options but with promising targets and these are being pursued. In adrenocortical cancer we are pursuing strategies that will hopefully lead to targeted therapies. We have been interested in novel chemotherapeutic agents that are toxic to the normal adrenal gland and have been working to identify the steps in the normal adrenal that might be responsible for activating compounds that might otherwise not be cytotoxic. The expression of unique enzymes as part of the steroid biosynthetic pathway are likely candidates, and we have identified in adrenal cancers, a high percentage that express levels of the enzymes that are comparable to those in the normal adrenal. We are pursuing a compound that is toxic to the normal adrenal based on this information. We are also seeking to identify strategies to modulate the expression of these genes in adrenal cancers, with the goal of up-regulating the expression of crucial enzymes so as to render the adrenal cancers vulnerable to these compounds. Our studies have demonstrated that depsipeptide increases the efficiency of adenoviral transgene expression in vitro in cancer cells, in hematopoietic cells and in human umbilical vein endothelial cells (HUVEC) and may be useful in cancer gene therapy. Treatment with minimally cytotoxic doses of depsipeptide increases CAR and av integrin RNA preferentially in cancer cells. We are also investigating the possibility that gents of this class or of a related class might be able to modulate the expression of what might be considered differentiated genes. In thyroid cancer we are expanding our effort to a basic/translational/clinical program that aims to help understand the mechanism of action of novel agents, and their targets in thyroid malignancies. We have begun this effort with translational studies aimed at identifying the best way in which to assess the extent of RET inhibition in medullary thyroid carcinomas (MTC) treated with tyrosine kinase inhibitors. Ongoing studies are designed to identify the best way in which to accomplish this. Clinically we have launched a combination therapy trial in MTC comprised of the proteasome inhibitor bortezomib and the VEGF, EGF, RET kinase inhibitor vandetanib in patients with refractory MTC. The goal of this study is to establi9sh the MTD in a phase I portion and then to conduct a randomized sturdy between vandetanib alone ands the combination of vandetanib with bortezomib. Translational studies designed to evaluate the extent of RET inhibition so as to ascertain whether this is indeed the target of vandetanib in this cancer are ongoing, and will be supported by the ongoing translational studies. Additional studies will be staring soon in other thyroid histologies, all with translational components. Finally, surprised by the change following the addition of HDAC inhibitors, we examined the ability of depsipeptide to modulate expression of thyroid specific genes. Two follicular (FTC 132 and FTC 136) and two anaplastic thyroid carcinoma cell lines (SW 1736 and KAT-4) were treated with a sub-cytotoxic concentration of depsipeptide (1 ng/ml). After three days, Tg and Na+/I- symporter (NIS) mRNA levels approached those of a normal thyroid. 125I accumulations indicated a functional NIS was induced. These in vitro results suggest depsipeptide or another HDAC inhibitor might be used clinically in thyroid carcinomas that do not to trap iodine, as an adjunct to radioiodine therapy a strategy currently under investigation in the clinic Finally with both poorly differentiated thyroid carcinomas and anaplastic thyroid carcinomas, therapeutic options are limited and largely unsuccessful. Their inability to trap iodine is thought to be a consequence of a loss of expression of the Na+/I- symporter (NIS). Our results suggest HDAC inhibitors up-regulate NIS transcription. Our clinical experience with depsipeptide has found it to be well tolerated, and the levels achieved greatly exceed those that modulated expression of the thyroid genes. A phase one trial to test this observation is ongoing.